Summary: In this Phase I program we will demonstrate the feasibility of an assay to identify subjects who have a high genetic risk of coronary artery disease (CAD) and sequelae of angina, myocardial infarction, heart failure and sudden death using a drop of whole blood spotted on filter paper (WBsf) and assayed directly without isolation of the DNA using a high throughput TempO-Seq DNA variant targeted sequencing assay, TempO- Vseq. The variant calls and genetic risk score (GRS) determined by the TempO-Vseq assay will be benchmarked against Infinium genotyping calls and GRS to establish performance. CAD is responsible for 1/3 of deaths in the US and world-wide. Genetic predisposition for CAD based on a polygenic GRS has been shown to be independent of conventional risk factors, including age. Large genotyping studies have been carried out that have shown that a polygenic GRS can predict risk of incident CAD events, and that prophylactic treatment with statin or adherence to a healthy lifestyle reduces incidence in subjects who are high risk. These studies have identified the variants that can be targeted to provide a GRS. The clinical rationale for a screening test based on GRS is that it can be carried out at any age, but if carried out any time before the age of 40, before clinical risk factors are typically evident, it can identify risk and afford the opportunity for early therapeutic prophylactic use of statins and/or pursuit of a healthy lifestyle. Both reduce the incidence of CAD, and if statin were to be prescribed to high-risk GRS subjects, would prevent 1 death for every 13 treated. Having identified the variants for a CAD screen to determine GRS, the need is for the lowest cost platform that provides the performance of current genotyping arrays and provides the best health economics of sample collection, shipping, storage, and assay. Advantages of the TempO-Vseq screen are expected to be 2x or greater reduction in cost, no proprietary hardware purchase required, simpler sample acquisition from a finger-prick (or if found superior in Phase II, buccal swab, or spit), simpler shipping and storage of filter paper rather than frozen blood, fully automated processing and data analysis, lower variant calling error rate than sequencing, and a weekly throughput per sequencer of >11,000 samples. The same screen augmented with additional variants could be used to identify high risk for atrial fibrillation (a leading cause of ischemic stroke), type 2 diabetes, and other contributors to CAD.